1. Field of the Invention
The present invention relates to amide derivatives of dihydrocaffeic acid and their application to pharmaceutical uses. More specifically, the present invention relates to amide derivatives of dihydrocaffeic acid which are capable of inducing production and secretion of a nerve growth factor (hereinafter referred to as NGF) in specific tissues in the brain and to pharmaceutical agents containing these derivatives as effective constituents for the prevention of the progression of degenerative diseases in the central nervous system and the therapeutic treatment thereof.
2. Description of the Prior Art
With extended average life expectancy, rapid progress in research has been made all over the world in order to establish methods for early diagnosis, ethiological study and therapeutic treatment of various gerontological diseases; degenerative diseases in the central nervous system are a major object of this research. In particular, senile dementia of Alzheimer type (hereinafter abbreviated to as SDAT), a typical disease of such diseases, is now becoming a big social problem because the number of the cases is markedly increasing, mainly in developed countries, and the patients suffer through a miserable progressive course. Although many researchers and clinicians have been intensively studying the pathology of this disease, particularly in recent years, the fundamental cause of the disease has not been elucidated and therefore no effective methods for the early diagnosis and treatment of the disease have been established.
However, a number of pathological observations demonstrates that the direct causes of the early characteristic symptoms of SDAT, such as memory failure and disorientation, are the progressive changes in large cell cholinergic nerve fibers which project into the memory and learning centers, i.e., the cerebral cortex and hippocampus, from the cerebral basal ganglia and dysfunctions in said controlled areas caused by this change. In fact, a few case reports showed that the symptoms were slightly improved by administering an acetylcholine biosynthesis precursor or a cholinesterase inhibitor as an activator to SDAT patients in order to activate the cholinergic system in the brain. However, in general, the observed effects were not so significant as expected.
Since discovery of NGF by R. Levi-Monterlcini, S. Cohen and others, considerable research on NGF has been carried out. To date, it has been proved by physiological experiments that NGF is an essential factor for differentiation and growth of sensory and sympathetic nerve cells in the peripheral nervous system, particularly in the embryonal period, and further for the survival of the sympathetic nerve cells and maintenance of their functions in the maturation period.
However, because NGF is a physiologically active substance which exists only in an extremely small quantity, accurate knowledge regarding distribution and movement of NGF in tissues, which directly demonstrates the action of NGF in the body, has not been attained in spite of intensive research for a long period of time. Only recently, a highly sensitive enzyme-linked immunosorbent assay (hereinafter referred to as ELISA) for an active subunit of NGF (beta-NGF, hereinafter simply designated as NGF) was developed and improved with sufficient sensitivity and specificity to study the matters described above (S. Furukawa et al.: J. Neurochem., 40, 734-744, 1983 and S. Korshing and H. Thoenen: Proc. Natl. Acad. Sci., USA, 80, 3513-3516, 1983).
Furthermore, the NGF gene was cloned and its structure was analyzed, which makes it possible to establish a method for the quantitative measurement of its messenger RNA (hereinafter abbreviated as mRNA) by using the complementary DNA (hereinafter abbreviated as cDNA) of beta-NGF (D. L. Shelton and L. F. Reichardt: Proc. Natl. Acad. Sci., USA, 81, 7951-7955, 1984 and R. Heumann et al.: EMBO J., 3, 3183-3189, 1984).
Then, using the techniques described above, it was proved that there is a positive correlation between the degree of control by the sympathetic nerve in the peripheral nervous system and expression of the NGF gene in the tissues being controlled.
More surprisingly, NGF is detected also in the central nervous system, particularly in the hippocampus, the neocortex, the septal area of the olfactory bulb and basal forebrain, the Broca's diagonal band and the large cell basal ganglia, and moreover mRNA concentrations are high in the hippocampus and the neocortex and are as low in the septal area of the basal forebrain as in other brain areas where NGF is not detected (S. Korshing et al.: EMBO J., 4, 1389-1393, 1985). Later these observations were re-examined one after another by other research groups (D. L. Shelton and L. F. Reichardt: Proc. Natl. Acad. Sci., USA 83, 2714-2718, 1986 and S. Whittemore et al.: Proc. Natl. Acad. Sci., USA, 83, 817-821, 1986).
These findings demonstrate that the NGF gene is expressed not only in the peripheral nervous system but also in the central nervous system and moreover that NGF is produced and secreted in the areas controlled by cholinergic nerve fibers which project into the neocortex and hippocampus, i.e., the memory and learning center, from the nucleus of origin of the cerebral ganglia, captured at the nerve endings and then brought to the cellular body of the nucleus of origin by reverse axon transport. It was proved by a series of physiological experiments that NGF is an essential factor for the survival of these cholinergic nerve cells and maintenance of their functions; it was thus proved from these observations that NGF specifically functions also in the central nervous system as one of the "nerve nutrition factors".
Later, these findings were re-examined by various research groups and also verified from research on NGF receptors and NGF distribution in the brain.
During the course of the research on the function of NGF in the central nerve system as a nerve nutrition factor, the present inventors concluded that although a direct cause of the disturbance in memory and learning, which is an early symptom of SDAT, may be progressive changes of the cholinergic nerve fibers and dysfunction caused by these changes in the areas being controlled, the disease may be caused more fundamentally by disturbance in production and secretion of NGF in these areas being controlled by responsible nerves.
In other words, the present inventors believe that marked improvement cannot be attained by conventional nosotrophic therapy for SDAT, for example by providing acetylcholine or by increasing availability of acetylcholine, but it may be far more effective as a therapy to secure the production and excretion of NGF in the cerebral cortex and hippocampus so as to stop a functionally vicious cycle established within the controlling nerves, if possible.
However, great pharmaceutical and pharmacological difficulties still exist in substitution therapy using NGF itself which is a protein having a molecular weight of more than 10,000 although a way of possible mass production of human type beta-NGF by cloning of the gene has opened. In particular, as to the application to the central nerve system, the prospect of development is still far from certain.
From the point of view mentioned above, for a substantial and effective NGF substitution therapy, it is of great importance to search for a low molecular weight molecule which can induce production and excretion of NGF in specified tissues. The present inventors have already reported on catechol derivatives which have this action (for example, Fukazawa: Japanese Patent Laid-open No. 53767/1990 and No. 152950/1990). Furthermore, there are reports by Furukawa et al. (Y. Furukawa et al.: J. Biol. Chem., 261, 6039, (1986) and FEBS Letters, 208, 258, (1986)).
As mentioned above, it is expected that compounds and modified compounds thereof, being modified based on pharmacological and pharmaceutical considerations, have a capability to promote production and secretion of NGF which functions as the "nerve nutrition factor" and acts on specific nerves in the tissues being controlled, and thus possibly increase the amount of available NGF to degenerated sites of the nerves by means of ordinary administration of said compounds, thereby recovering the functions of said specific nerves. In particular, use of these compounds for the therapy of SDAT, a disease in the central nervous system for which fundamental therapy has not yet been established, is ideal. If treated in the early stage of the disease and administered at the peripheral system, these compounds enhance capability of NGF production and secretion in the cerebral cortex and the hippocampus area in the central nervous system, prevent the progress of characteristic changes in the nerves being controlled by NGF, i.e., the cholinergic nerve system, and promote repair of damaged nerve cells or re-control by remaining nerve cells, thereby providing a revolutionary therapy based on the new action concept attributed to flexibility of brain functions.
However, later, research showed that none of the catechol derivatives so far reported were satisfactorily absorbable or retainable when orally administered. The present inventors continued their study in order to solve this problem and consequently found that the compounds of the present invention are increasingly absorbable when orally administered and their retention in the blood is highly improved as compared to the compounds described in Japanese Patent Laid-open No. 152950/1990 and No. 99046/1991 which were applied previously by the present inventors. Furthermore, it was found that the amount of NGF increased in various parts of brain when the compounds of the present invention were orally administered to rats, with which the present invention was deemed to be completed.